Euchromatin histone methyltransferase 1 regulates cortical neuronal network development

Martens, Marijn B.; Frega, Monica; Classen, Jessica; Epping, Lisa; Bijvank, Elske; Benevento, Marco; Bokhoven, Hans van; Tiesinga, Paul; Schubert, Dirk W.; Kasri, Nael Nadif

doi:10.1038/srep35756

Cited by 36 publications

(34 citation statements)

References 64 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We found that for control iNeuron networks the pattern of activity changed progressively over a period of several weeks ( Fig. 2B-F), similar to what we have observed previously in rodent neuronal cultures 29 . In particular, during the first three weeks of differentiation, (CV) of the inter-burst interval (P<0.0001) ( Fig.…”

Section: Neuronal Network Of Ks Ineurons Show An Aberrant Pattern Ofsupporting

confidence: 88%

“…Indeed, we found that network bursts also occurred with a lower frequency, longer duration and irregular pattern in dissociated neuronal networks from either embryonic rats (i.e. where Ehmt1 was downregulated through RNA interference 29 ). This indicates that some network parameters are consistently and similarly altered in divergent KS models.…”

Section: Discussionmentioning

confidence: 85%

See 1 more Smart Citation

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Frega

Linda

Keller

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Epigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects.Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs.Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.Advances in human genetics over the past decade have resulted in the identification of hundreds of genes associated with intellectual disability (ID) and autism spectrum disorder (ASD) 1 . Within this group of newly identified genes the number of chromatin regulators is remarkably high 2-4 . These regulators are engaged in genome-wide covalent DNA modifications, post-translational modifications of histones, and control of genomic architecture and accessibility 5 . Several ASD/IDlinked chromatin regulators directly interact with one another to form larger complexes, regulating chromatin structure to control the expression of genes important for neurodevelopment and/or neuroplasticity 3 . Despite considerable progress in elucidating the genetic architecture of many neurodevelopmental disorders (NDDs), a large gap still exists between the genetic findings and deciphering the cellular or molecular pathobiology 6 . In particular, we require a better understanding of the relevance of genetic changes with respect to their downstream functional consequences and whether there is overlap between different patients within the clinical spectrum 6 .Kleefstra syndrome (KS) (OMIM#610253) is an example of a rare monogenic NDD with ID, ASD, hypotonia and dysmorphic features as hallmark phenotypes 7-9 . KS is caused by heterozygous de novo loss-of-functio...

show abstract

Section: Neuronal Network Of Ks Ineurons Show An Aberrant Pattern Ofsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 85%

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Frega

Linda

Keller

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, EHMT1 can be viewed as a dynamic regulatory histone mark instead of a generic heterochromatin mark [Benevento et al, 2016]. EMHT1 has been demonstrated to be essential for neural network activity, action potential coherency, and burst time during brain development [Bart Martens et al, 2016]: EHMT1 loss may therefore potentially lead to structural and functional anomalies in the developed brain.…”

mentioning

confidence: 99%

New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review

Ciaccio

Scuvera

Tucci

et al. 2018

Cytogenet Genome Res

View full text Add to dashboard Cite

Kleefstra syndrome (KS) is a rare genetic condition resulting from either 9q34.3 microdeletions or mutations in the EHMT1 gene located in the same genomic region. To date, approximately 100 patients have been reported, thereby allowing the core phenotype of KS to be defined as developmental delay/intellectual disability, generalized hypotonia, neuropsychiatric anomalies, and a distinctive facial appearance. Here, to further expand the knowledge on genotype and phenotype of this condition, we report 2 novel cases: one patient carrying a 46-kb 9q34.3 deletion and showing macrocephaly never described in KS, and a second patient carrying a classic 9q34.3 deletion, presenting with a previously unreported skeletal feature (postaxial polydactyly of the right foot) and an unusual brain anomaly (olfactory bulb hypoplasia) observed via magnetic resonance imaging. Further, we provide a review of the current literature regarding KS and compare these 2 patients with those previously described, thereby confirming that the genotype-phenotype correlation in KS remains difficult to determine.

show abstract

“…The mouse homolog has been shown to specifically regulate the expression of several activity-dependent genes in the hippocampus following fear conditioning 10 . Furthermore, it has been shown to be critically involved in homeostatic synaptic scaling in vitro and in the developing visual cortex in vivo 11,12 . Ehmt1 +/mice recapitulate core features of the human phenotype: they show delayed postnatal development and facial and cranial abnormalities that correspond to the phenotype observed in human patients 13 .…”

Section: Introductionmentioning

confidence: 99%

The Object Space Task reveals a dissociation between semantic-like and episodic-like memory in a mouse model of Kleefstra Syndrome

Schut¹,

Alonso²,

Smits³

et al. 2019

Preprint

View full text Add to dashboard Cite

One Sentence Summary:, Ehmt1 +/mice show decreased exploration and episodic-like memory but increased semantic-like memory In the Object Space Task. (143 of 150) AbstractKleefstra syndrome is a disorder caused by a mutation in the EHMT1 gene characterized in humans by general developmental delay, mild to severe intellectual disability and autism. Here, we characterized semantic-and episodic-like memory in the Ehmt1 +/mouse model using the Object Space Task. We combined conventional behavioral analysis with automated analysis by deep-learning networks, a session-based computational learning model and a trial-based classifier. Ehmt1 +/mice showed more anxiety-like features and generally explored objects less, but the difference decreased over time. Interestingly, when analyzing memory-specific exploration, Ehmt1 +/show increased expression of semantic-like memory, but a deficit in episodic-like memory. A similar dissociation of semantic and episodic memory performance has been previously reported in humans with autism. Using our automatic classifier to differentiate between genotypes, we found that semantic-like memory features are better suited for classification than general exploration differences. Thus, detailed behavioral classification with the Object Space Task produced a more detailed behavioral phenotype of the Ehmt1 +/mouse model.

show abstract

Euchromatin histone methyltransferase 1 regulates cortical neuronal network development

Cited by 36 publications

References 64 publications

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review

The Object Space Task reveals a dissociation between semantic-like and episodic-like memory in a mouse model of Kleefstra Syndrome

Contact Info

Product

Resources

About